The American Academy of Pediatrics guidelines for intervention in patients with hyperbilirubinemia (total serum bilirubin concentration [TSB] modified by clinical factors) are based on sparse published clinical evidence and do not consider the likely modifying effects of serum bilirubin binding, unbound bilirubin concentration, or bilirubin photoisomers (which may comprise >20% of total serum bilirubin in patients receiving phototherapy). The low prevalence of severe hyperbilirubinemia and encephalopathy in the United States has precluded a systematic study of these risk factors in this country. Although Egyptian physicians use AAP guidelines for intervention, early postnatal discharge of infants without adequate monitoring and predisposing population risk factors for jaundice have resulted in a very high prevalence of babies admitted with severe hyperbilirubinemia and a high incidence of acute and residual encephalopathy. The primary goal of this collaborative R21 pilot study, developed with Egyptian partners, is to establish the relative importance of total serum bilirubin, unbound (free) bilirubin, photoisomer concentrations, and clinical risk factors in predicting acute signs of neurotoxicity (neurological signs, failed hearing screens) in patients readmitted with TSB >25 mg/dL, and the presence of residual neurological signs and abnormal brain- stem auditory evoked responses at one month of age. Five collaborating university NICUs in Egypt, led by Cairo University, will provide clinical and basic laboratory data. Experimental chemistries (free bilirubin determined by three different methods, photoisomers, and carboxyhemoglobin as an indicator of hemolysis) will be performed in research laboratories at Stanford University. Multiple logistic regression will be used to select and weight risk factors, and ROC curves will used to compare sensitivity and specificity of different predictive paradigms. The long term goal is to expand and extend this study for 18-24 month follow up and obtain sufficient data to ethically justify a randomized comparison of a new paradigm with AAP guidelines for intervention. The ultimate goal is to improve selection of patients in need of treatment and reduce unnecessary hospital admissions of jaundiced newborns. PUBLIC HEALTH RELEVANCE: Current guidelines for treating jaundiced newborns are based on limited evidence linking total serum bilirubin (TSB) and clinical factors to brain damage (kernicterus). Because of the low specificity of these predictors, an estimated 800-1000 newborns are hospitalized and treated to prevent a single case of kernicterus. In an effort to improve the selection of patients in need of treatment, this study will examine the ability of biochemical and clinical risk modifiers, including TSB, free bilirubin (TSB not bound to serum proteins), and bilirubin photoisomer concentration (formed by phototherapy), to predict brain injury in a population with high prevalence of severe hyperbilirubinemia and kernicterus.